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Topiramate Treatment for Heavy Drinkers: Moderation by a GRIK1 Polymorphism
Henry R. Kranzler, M.D.; Jonathan Covault, M.D., Ph.D.; Richard Feinn, Ph.D.; Stephen Armeli, Ph.D.; Howard Tennen, Ph.D.; Albert J. Arias, M.D.; Joel Gelernter, M.D.; Timothy Pond, M.P.H.; Cheryl Oncken, M.D., M.P.H.; Kyle M. Kampman, M.D.
Am J Psychiatry 2014;171:445-452. doi:10.1176/appi.ajp.2013.13081014
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Dr. Kranzler has served as a consultant to or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer, and Roche; he is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which is supported by Abbott, Lilly, Lundbeck, and Pfizer. Dr. Oncken has received study supplies from Pfizer for a smoking cessation study. All other authors report no financial relationships with commercial interests.

Supported by National Institutes of Health grants P60 AA03510 and K24 AA13736, from the National Institute on Alcohol Abuse and Alcoholism, and the VISN 4 Mental Illness Research, Education, and Clinical Center of the U.S. Department of Veterans Affairs.

ClinicalTrials.gov registry number, NCT00626925 (www.clinicaltrials.gov).

From the Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia; VISN 4 Mental Illness, Research, Education, and Clinical Center, Philadelphia Veterans Administration Medical Center, Philadelphia; the Alcohol Research Center, Department of Psychiatry, University of Connecticut School of Medicine, Farmington, Conn.; the Frank Netter School of Medicine, Quinnipiac University, Hamden, Conn.; the Department of Psychology, Fairleigh Dickinson University, Teaneck, N.J.; the Department of Community Medicine and Healthcare, University of Connecticut School of Medicine, Farmington, Conn.; the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn.; VA Connecticut Healthcare System, West Haven, Conn.; and the Department of Medicine, University of Connecticut School of Medicine, Farmington, Conn.

Address correspondence to Dr. Kranzler (kranzler@mail.med.upenn.edu).

Copyright © 2014 by the American Psychiatric Association

Received August 02, 2013; Revised October 08, 2013; Accepted November 25, 2013.

An erratum to this article has been published | view the erratum

Objective  Topiramate has been shown to reduce drinking and heavy drinking in individuals with alcohol dependence whose goal was to stop drinking. The authors evaluated the efficacy and tolerability of topiramate in heavy drinkers whose treatment goal was to reduce drinking to safe levels.

Method  A total of 138 individuals (62.3% men) were randomly assigned to receive 12 weeks of treatment with topiramate (N=67), at a maximal daily dose of 200 mg, or matching placebo (N=71). Both groups received brief counseling to reduce drinking and increase abstinent days. It was hypothesized that topiramate-treated patients would be better able to achieve these goals, and it was predicted that based on prior research, the effects would be moderated by a single nucleotide polymorphism (rs2832407) in GRIK1, encoding the kainate GluK1 receptor subunit.

Results  The rate of treatment completion was 84.9% and equal by treatment group. Topiramate treatment significantly reduced heavy drinking days and increased abstinent days relative to placebo. Patients receiving topiramate also had lower concentrations of the liver enzyme γ-glutamyl transpeptidase and lower scores on a measure of alcohol-related problems than the placebo group. In a European American subsample (N=122), topiramate’s effect on heavy drinking days was significantly greater than that for placebo only in rs2832407 C-allele homozygotes.

Conclusions  These findings support the use of topiramate at a daily dose of 200 mg to reduce heavy drinking in problem drinkers. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment and provide an important personalized treatment option. The pharmacogenetic findings also implicate the kainate receptor in the mechanism of topiramate’s effects on heavy drinking.

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FIGURE 1. Mean Heavy Drinking Days Per Week by Medication Groupa

a There was a significant main effect of medication group (F=23.37, df=1, 1399, p<0.001) and interaction of medication group-by-treatment week (F=19.91, df=1, 1399, p<0.0001). The standard error of the mean is represented.

FIGURE 2. Mean Abstinent Days Per Week by Medication Groupa

a There was a significant main effect of medication group (F=4.63, df=1, 1398, p=0.03) and interaction of medication group-by-treatment week (F=6.26, df=1, 1398, p=0.01). The standard error of the mean is represented.

FIGURE 3. Mean Heavy Drinking Days Per Week by Medication Group and rs2832407 Genotypea

a There was a significant medication group-by-genotype interaction (F=5.50, df=2, 1227, p=0.004). The standard error of the mean is represented.

FIGURE 4. Mean Abstinent Days Per Week by Medication Group and rs2832407 Genotypea

a The interaction of medication group-by-genotype group was not statistically significant. The standard error of the mean is represented.

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TABLE 1.Demographic and Pretreatment Clinical Measures
Table Footer Note

a For continuous measures, t tests were used; chi-square tests were used for categorical measures.

Table Footer Note

b Income data were missing for one topiramate patient.

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c Data represent the proportion of the 90 days preceding the screening visit.

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TABLE 2.Baseline Demographic and Clinical Characteristics by Genotype (rs2832407) and Treatment Assignment of European American Patients (N=122)
Table Footer Note

a The genotype frequencies in European Americans were consistent with Hardy-Weinberg equilibrium expectations (χ2=0.61, df=2, p=0.74).

Table Footer Note

b There was statistical significance for a main effect between groups (p=0.04) (topiramate patients: mean age=50.7 years [SD=7.3]; placebo patients: mean age=53.1 years [SD=7.3]).

Table Footer Note

c The data represent information preceding the screening visit.



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